Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

HRID 1863914Notes

Reaction equation

HRID 1863914 reaction equation
[NH2:1][CH2:2][CH:3]=[CH:4][C:5]1[NH:6][C:7](=[O:29])[C:8]2[C:9]3[N:18]([CH3:19])[C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[CH3:28])=[N:16][C:10]=3[CH:11]=[CH:12][C:13]=2[C:14]=1[CH3:15].[CH3:30][P:31]1(=[O:40])[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(N(CC)CC)C.CN(C)C=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]2[N:18]([CH3:19])[C:9]3[C:8]4[C:7](=[O:29])[NH:6][C:5]([CH:4]=[CH:3][CH2:2][NH:1][C:37]([CH:34]5[CH2:35][CH2:36][P:31]([CH3:30])(=[O:40])[CH2:32][CH2:33]5)=[O:38])=[C:14]([CH3:15])[C:13]=4[CH:12]=[CH:11][C:10]=3[N:16]=2)=[C:22]([CH3:28])[CH:23]=1

Participants

6

Reactant 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 579733021-Methyl-1-oxo-1lambda5-phosphinane-4-carboxylic acidHCID 668324547-(3-Amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

Product 1

HCID 668326372-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-oneYield 26%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8471TriethylamineSolvent2×

Procedure

To scintillation vial with a magnetic stir-bar was added 7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (68 mg, 173 mmol), followed by dimethylformamide (DMF) (1.0 mL) and triethylamine (TEA) (0.25 mL). To a separate scintillation vial was added 1-methyl-1-oxo-1λ5-phosphinane-4-carboxylic acid (130 mg, 0.74 mmol, mixture of cis/trans isomers), HATU (300 mg, 0.79 mmol), and DMF (2.0 mL), followed by TEA (0.25 mL). The solution was sonicated until most of the solids were dissolved. A solution of the activated ester (1.0 mL, or roughly half) was transferred to the solution of amine and stirred for 2.5 hours at room temperature, after which time the starting material was completely consumed as determined by LC-MS. The reaction mixture was quenched by addition of water (0.5 mL), then acidified with TFA. The mixture was filtered (syringe membrane filter) and purified directly by reverse-phase HPLC to provide 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (24.9 mg, 26%) as a mixture of cis/trans isomers. 1H NMR (400 MHz, d6-DMSO) δ 11.12 (s, 1H), 10.55 (s, 1H), 8.21-8.17 (m, 1H), 7.74 (d, J=8.6Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.55 (dd, J1=5.9 Hz, J2=9.0 Hz, 1H), 7.27 (td, J1=2.7 Hz, J2=8.6 Hz, 1H), 6.66 (d, J=15 Hz, 1H), 6.55-6.49 (m, 1H), 4.18 (s, 3H), 3.92 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 2.35-2.30 (m, 1H), 2.08-1.90 (m, 6H), 1.78-1.65 (m, 2H), 1.52-1.47 (m, 3H); ESMS m/z: found, 550 (M+1)+.

Workup

  1. customThe solution was sonicated until most of the solids
  2. dissolutionwere dissolved
  3. customafter which time the starting material was completely consumed
  4. customThe reaction mixture was quenched by addition of water (0.5 mL)
  5. filtrationThe mixture was filtered
  6. filtration(syringe membrane filter)
  7. custompurified directly by reverse-phase HPLC

Sources & evidence

ORD record
ord-c9f816cb25aa4c77924cee028c4428fc
Source dataset
uspto-grants-2009_12
Patent number
US07625880B2

Reaction notes

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